ABSTRACT In previous phases of this project, we have developed, validated, and normed a comprehensive battery of socioemotional tests specifically to evaluate the socioemotional symptoms of patients with behavioral variant frontotemporal dementia (bvFTD) and related syndromes. However, to better prepare for bvFTD-focused clinical trials, for Aim 1 we will use our previously collected socioemotional and brain imaging data (159 bvFTD/81 svPPA patients) and add longitudinal timepoints (135 new observations in bvFTD and 83 in svPPA) to determine the value of socioemotional testing for predicting patients? pathological trajectories. We hypothesize that socioemotional measures will be sensitive to early behavioral changes in bvFTD and svPPA patients, and will show progressive changes over the disease course that will correspond to structural and functional changes in the selectively vulnerable salience (SN) and semantic appraisal (SAN) networks. We will see if risk scores using socioemotional measures will perform better than scores using neuroimaging alone at predicting 1) rapid progression, 2) caregiver burden, and 3) tau vs.TDP neuropathology. Also in previous phases of this R01, we have used this rich socioemotional dataset to model how the SN and SAN networks contribute to the diverse socioemotional phenotypes within the FTD syndromes, demonstrating that trait intrinsic functional connectivity in these networks is a strong predictor of many socioemotional functions in both patients and healthy individuals. Still, little is known about how neurodegeneration changes the functional dynamics of these two ICNs to alter empathy, and we still lack neuroscientifically precise methods for measuring these circuits? integrity. For Aim 2, we will investigate neural mechanisms using a task-based fMRI to further elucidate the functional network dynamics of the SN and SAN during naturalistic socioemotional reasoning, and to investigate the mechanisms by which neurodegeneration of these networks leads to empathy deficits patients. We hypothesize that while viewing videos requiring naturalistic socioemotional processing, neurologically healthy older controls (N=20) will show a pattern of activation in which a) SN activity will influence activation of other networks involved in socioemotional reasoning, including the DMN and the FPN, and a) SAN activity will influence SN activation, but in contrast, patients with bvFTD (N=20) and svPPA (N=20) will show alterations of these network dynamics relative to controls. We will investigate whether greater SN and SAN activity while watching the scenarios will predict more accurate empathic decisionmaking and better real-life empathic behavior, and clarify the relationship between SN and SAN intrinsic connectivity and dynamic activity. Finally, for Aim 3, we will pilot a novel cortical mapping paradigm to evaluate the integrity of bvFTD and svPPA patients? cortical representations of socioemotional semantics, hypothesizing that patients with svPPA will have poorer map integrity than patients with bvFTD, and both groups will have poorer map integrity than older NCs. We will also investigate whether semantic map integrity predicts empathic behavior, and whether the maps are sensitive to disease progression.